TAM Signaling in the Nervous System

Abstract

Tyro3, Axl and Mertk are members of the TAM family of tyrosine kinase receptors. TAMs are activated by two structurally homologous ligands GAS6 and PROS1. TAM receptors and ligands are widely distributed and often co-expressed in the same cells allowing diverse functions across many systems including the immune, reproductive, vascular, and the developing as well as adult nervous systems. This review will focus specifically on TAM signaling in the nervous system, highlighting the essential roles this pathway fulfills in maintaining cell survival and homeostasis, cellular functions such as phagocytosis, immunity and tissue repair. Dysfunctional TAM signaling can cause complications in development, disruptions in homeostasis which can rouse autoimmunity, neuroinflammation and neurodegeneration. The development of therapeutics modulating TAM activities in the nervous system has great prospects, however, foremost we need a complete understanding of TAM signaling pathways.

Keywords: Gas6; PROS1; TAM receptors; TAM signaling; homeostasis; immune; nervous system; neurodegeneration; neuroinflammation; phagocytosis; protein S.

Fig. 1

Opposing roles for PROS1 and GAS6 in NSC choice points. Different roles for the TAM agonists PROS1 and Gas6 were revealed through their genetic deletion. Opposing effects are seen on NSC self-renewal, where GAS6 deletion reduces the number of NSCs [40] but PROS1 deletion increased NSC self-renewal [24]. NSC “stemness” is maintained by PROS1, which inhibits NSC proliferation [25], but Gas6 promotes NSC proliferation [40]. PROS1 deletion led to an increase in astrogenesis, indicating its instructive role in the neurogenic fate lineage [25]. By contrast, Gas6 deletion had no effect on the cell fate of differentiated cells [40]. This delicate balance between Gas6 and PROS1 may contribute to NSC homeostasis and neurogenesis.

Fig. 2

PROS1 regulates numerous aspects of NSC biology through multiple signaling pathways. Schematic of the dentate gyrus granular layer, indicating the influence of PROS1 on different phases of adult NSCs and neurogenesis. Quiescent NSCs (qNSCs) are glia-like and present with a dendritic arbor spanning the granular layer. Quiescent NSCs express PROS1, considered a stem-cell maintenance factor. PROS1 regulates Notch1 signaling, and suppresses NSC proliferation [25]. Upon integration of various signals, qNSCs begin to amplify through proliferation. Amplifying NSCs (aNSCs) also express PROS1, which promotes NSC differentiation by inhibiting Bmi-1, a transcriptional repressor of p16 and p19 which allows for continuation of self-renewing cell divisions [24]. PROS1 expression in differentiated NSCs promotes a neural cell fate over astrogenesis [25]. Within the neurogenic niche, PROS1 is highly expressed by microglia, where it is thought to regulate cytokine expression and phagocytosis of apoptotic neurons, thus influencing neurogenesis in a non-cell autonomous manner.

Fig. 3

The role of TAM signaling in maintaining homeostasis, regulating inflammation and preventing neurodegeneration. At steady state, the TAM pathway mediates homeostasis via regulation of NSCs, microglial activity, myelination and phagocytosis. Upon injury, such as acute trauma, a demyelination event or neurodegenerative conditions, inflammation is instigated which may induce neurogenesis, elevated cytokine secretion, microglial and astrocytic gliosis, oligodendrocyte damage and demyelination. If unresolved, primary injury further develops into secondary injury with high toxicity, necrosis and may potentially develop into a chronic inflammatory condition, with activation of microglia and astrocytes, demyelination and toxin release before a new homeostasis is reached with accompanying tissue repair. Alternatively, primary injury may be resolved without secondary injury. TAM signaling is involved in various aspects of homeostasis and tissue repair, as detailed in the main text.